Abstract Malaria remains one of the most important global health challenges, with an estimated 3 billion people at risk of infection, leading to approximately 250 million cases and 1 million deaths each year, with a majority of the disease burden concentrated in sub-Saharan Africa. Since its establishment in Uganda in 2005, the U.S. President's Malaria Initiative has been highly successful in expanding the coverage of proven effective malaria control interventions. Despite these improvements, the burden of malaria remains very high in Uganda with no clear evidence of reductions in morbidity and mortality. There remains a great need to systematically evaluative the effectiveness of current malaria control interventions and investigate new interventions. The proposed program is intended to expand the Centers for Disease Control and Prevention network of collaborating institutes for both research and technical assistance to targeted African countries, with a particular focus on research to advance malaria control efforts. The Uganda Malaria Surveillance Project (UMSP) was established in 2001 with the purpose of creating a multi-site surveillance system for monitoring antimalarial drug efficacy and safety, malaria related morbidity and mortality, and building capacity for facility- based management of malaria with the goal of providing sustainable progress in malaria control. In response to this announcement, UMSP is proposing the following four separate research studies to help guide malaria policy decision making in Uganda: 1) We will perform an intervention study using an interrupted time series study design to test the hypothesis that a package of interventions including laboratory-based treatment decision making, IV artesunate, and standardized dosing and administration will improve patient outcomes compared to current practices for children hospitalized with complicated malaria. 2) We will perform a clinical trial to measure the in vivo efficacy of sulfadoxine-pyrimethamine (SP) for the clearance of asymptomatic parasitemia in pregnant women as a means of evaluating the effectiveness of intermittent preventive therapy with SP in pregnancy. 3) We will perform randomized clinical trials at multiple sites in Uganda to compare the efficacy and safety of artemether-lumefantrine and dihydroartemisinin-piperaquine for the treatment of uncomplicated falciparum malaria. 4) We will prospectively assess the coverage of key malaria control interventions (including insecticide treated bed nets, indoor residual spraying of insecticide, and artemisinin- based combination therapy) and measure metrics of malaria transmission, infection, and disease at multiple sites in Uganda. Statistical techniques will be used to estimate the impact of changing coverage levels of control interventions on our outcome measures.